Investigating Mechanistic Pathways involved in Neuroimmune Dysregulation and Neuropathic Pain Susceptibility due to Prenatal Alcohol Exposure

Pritha, Ariana; Joshua J. Sanchez; Jacob E. Sanchez; Suzy Davies; Daniel D. Savage; Nikolaos Mellios; Shahani Noor; and Erin D. Milligan. “Investigating Mechanistic Pathways involved in Neuroimmune Dysregulation and Neuropathic Pain Susceptibility due to Prenatal Alcohol Exposure.” (2


Neuropathic pain is a chronic pain condition resulting from damaged peripheral nerves that induces allodynia (pathological touch sensitivity). Our previous studies suggest that prenatal alcohol exposure (PAE) is a risk factor for allodynia. In contrast to control rats, adult PAE rats with minimal nerve injury develop allodynia. Nerve-injured PAE rats display heightened peripheral and central nervous system (CNS) immune cell-derived proinflammatory cytokine production that consequently results in allodynia. This suggests that PAE dysregulates peripheral immune and CNS glial cell function to over-respond to subtle immune challenges leading to allodynia. However, gene expression profiles underlying dysregulated neuroimmune activity due to PAE are poorly understood.

For the current study, the bioinformatics software, Ingenuity Pathway Analysis (IPA), was used to gain insight into key pathways and molecular targets underlying PAE’s effects on dysregulated neuroimmune function. Non-coding circular RNAs (circRNAs) are novel modulators of mRNA expression regulating CNS glial-immune function. Therefore, we hypothesized that circRNAs might be associated with critical neurological and immune dysfunction induced by PAE. Through IPA we identify the canonical pathways, diseases, and molecular functions, associated with the gene networks altered by PAE and nerve injury.

Our microarray data identified 114 circRNAs that were differentially expressed in the spinal cord from PAE rats than in control rats following minor nerve injury, with a p value of <0.05 and with a fold change >1.5. Additionally, our data identified 15 circRNAs in blood leukocytes that displayed significantly different expression patterns as a long-term consequence of PAE, in the absence of any injury. Analysis of “top networks” of the genes associated with these differentially expressed circRNAs identified distinct canonical pathways including NF-κB, which is activated by innate immune receptor TLR4 signaling. These results suggest that circRNA dysregulation could be a novel underlying mechanism of PAE-induced neuroimmune dysregulation.

Non-expert Summary:

Alcohol consumption during pregnancy causes developmental disabilities called Fetal Alcohol Spectrum Disorders (FASD). Individuals with FASD also display increased sensory abnormalities. Using a preclinical model of nerve injury, pathological light touch sensitivity (neuropathic pain) due to prenatal alcohol exposure (PAE) was studied. Here, we have utilized bioinformatic software to gain critical insights into key immune pathways involved in PAE-related dysfunction and neuropathic pain. Understanding these mechanisms are crucial for developing therapies for FASD-related sensory disorders.

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